Congestive heart failure is a growing public health problem affecting over 5 million people in the United States. Thromboembolic events, including stroke, are a major cause of morbidity and mortality in patients with heart failure.1 The annual risk of a thromboembolic event with mild to moderate heart failure and sinus rhythm ranges from 1.5-2.5% and exceeds 5% in severe disease.2,3 Thromboembolus formation in heart failure has historically been ascribed to blood stasis within the dilated cardiac chambers.4 Stasis alone, however, cannot fully explain intracardiac thrombus formation as even patients with heart failure and preserved systolic function remain at increased risk for stroke compared to those without heart failure.5 While recent evidence does suggest that heart failure may be associated with a mild degree of hypercoagulation6, what has received relatively little attention and yet may be a significant contributor to intracardiac thrombus formation is the third arm of Virchow's triad-dysfunction of the endocardial endothelium.
Thrombomodulin (TM) is a 100 kD membrane glycoprotein that is a major regulator of vascular thromboresistance.7 It is expressed in abundance by vascular endothelial cells, including those comprising the endocardium.8 binds thrombin and renders it incapable of enzymatically cleaving fibrinogen or activating cellular thrombin receptors but enables the activation of circulating protein C. Activated protein C (APC) degrades factors Va and XIIIa of the coagulation cascade, potently inhibiting further thrombin generation. Deletion of the TM gene causes lethal thrombosis in mice and the acquired loss of TM in humans is thought to contribute to the thrombotic manifestations of bacterial sepsis, radiation enteropathy and coronary atherosclerosis.9-11 
Autologous vein grafts are the most frequently used conduits for coronary and peripheral arterial bypass surgery. Compared with arterial grafts, vein grafts suffer a significantly higher failure rate that limits their clinical efficacy. One-and 12-month failure rates for coronary bypass vein grafts approach 12% and 20%, respectively, and are predominantly due to occlusive thrombosis. Late vein graft failure is due mainly to neointimal hyperplasia and accelerated atherosclerosis. Although surgical trauma and technical factors have often been invoked as possible causes of early graft failure, little is known about changes that may occur to the graft endothelium that might predispose to thrombosis. Thrombomodulin is down-regulated in vein grafts. Reduction in its expression facilitates local thrombin generation that predisposes to thrombotic graft occulusion.13 Moreover, thrombomodulin protein and gene expression highly correlate with changes in wall tension, such as occur when veins grafts are exposed to arterial pressure.12 
We recently identified pressure-induced vascular stretch as a novel and potent inhibitory stimulus for endothelial TM expression.12 This was first observed in rabbit vein segments implanted into the arterial circulation where TM protein expression decreased by 95% and resulted in increased local thrombin generation and microthrombus formation. 13 
There is a continuing need in the art to decrease stroke risk in patients with congestive heart failure, valvular heart disease, and atrial fibrillation without subjecting them to the risks of systemic anticoagulation. There is a continuing need in the art to improve the success rate of vein grafts for arterial bypass surgery.